Functionalized Polymers Using Protected Thiols

ABSTRACT

A process for the preparation of functional molecules using the thiol-ene coupling reaction and a process for the preparation of protected functional thiols, specifically thioesters is provided. The methods may be used to make functional polymers and other molecules. The method of making a functionalized polymer using a thiol-ene reaction comprises: providing a functionalized thioester having the following formula: 
     
       
         
         
             
             
         
       
     
     wherein R is a functional group and COR′ is a protecting group; cleaving the functionalized thioester, forming a functional thiol and an acyl group; providing a polymer having a pendant vinyl group; and reacting the polymer with the functional thiol whereby a functionalized polymer is formed, wherein the functional thiol is not isolated prior to reacting with the polymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 12/961,136,filed Dec. 6, 2010, which is a divisional of application Ser. No.12/251,708, filed Oct. 15, 2008, which takes priority from U.S.provisional application Ser. No. 60/998,980, filed Oct. 15, 2007, herebyincorporated by reference.

STATEMENT ON FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

This invention relates to functional polymers and functional protectedthiol compounds, methods of preparation and use.

Functionalization of polymers having pendant vinyl groups usingthiol-ene coupling is a powerful and versatile method to preparewell-defined polymeric materials with tailored properties. However,commercially available mercaptans are limited to a select few functionalgroups. Methods of preparing polymers having a variety of functionalgroups are needed.

SUMMARY OF THE INVENTION

According to the present invention there is provided a process for thepreparation of functional polymers and other molecules using thethiol-ene coupling reaction and a process for the preparation ofprotected functional thiols, specifically thioesters.

Generally the method of making functional polymers comprises reacting aprotected functional thioester with a deprotecting agent and a polymerhaving one or more pendant vinyl groups.

The protected functional thioesters prepared using the methods of theinvention can be stored and used when desired by deprotecting andreacting with a desired molecule such as a polymer having one or morependant vinyl groups.

More specifically, provided is a method of making a functionalizedpolymer using a thiol-ene reaction comprising: providing afunctionalized thioester having the following formula:

wherein R is a functional group and COR′ is a protecting group; cleavingthe functionalized thioester, forming a functional thiol and an acylgroup; providing a polymer having a pendant vinyl group; and reactingthe polymer with the functional thiol whereby a functionalized polymeris formed, wherein the functional thiol is not isolated prior toreacting with the polymer. In an embodiment, the cleaving step isperformed by reacting the functionalized thioester with a cleavingagent. In an embodiment, the cleaving agent is hydrazine. In anembodiment, the hydrazine is a hydrazine salt or solution thereof. In anembodiment, the hydrazine salt is hydrazine acetate. In an embodiment,the hydrazine acetate is formed from reaction of hydrazine HCl withNaOAc in DMF. In an embodiment, the protecting group is an acetyl orbenzoyl group. The protected functional thioester is deprotected insituin the reaction and is not isolated as a separate thiol molecule. In anembodiment, the method of making a functionalized polymer is a one-potreaction.

The methods of the invention can be used to functionalize othermolecules having one or more vinyl groups by one of ordinary skill inthe art without undue experimentation. The methods of the invention canbe used to add a functional group to a molecule having a single vinylgroup available for reaction, for example. For example, in molecularsynthesis of fine chemicals and drugs a C—S bond is often desired. Themethods described here can be used to conveniently add a functionalgroup in a synthetic pathway.

The polymer having a pendant vinyl group is a polymer having one or morevinyl groups available for reaction. In an embodiment, the polymer is apolybutadiene. In an embodiment, the polymer comprises a 1,2polybutadiene unit. In an embodiment, the polymer comprises a polymer orcopolymer of butadiene having 1,2-polybutadiene units. As known in theart, polybutadienes may be prepared with a wide distribution ofmolecular weight and density of double bonds. The use of all suchdistributions and densities are intended to be included herein. Thenumber of pendant vinyl groups and the extent of reaction as determinedby reaction conditions (specifically the concentration of reactants andthe reaction time) determine the final structure obtained afterreaction. These variables are well known in the art. Other usefulpolymers include any polymer or copolymer of butadiene, isoprene,2-n-heptyl-1,3-butadiene, ethylene, isobutylene, 1-butene,acrylonitrile, methacrylonitrile, crotonitrile, vinyl acetate, vinylbenzoate, vinyl methyl ether, vinyl n-butyl ether, allyl propionate,allyl benzoate, allyl methyl ester or 5-vinyl-2-norbornene. Inembodiments, useful polymers include: polymers and copolymers ofstyrene, vinyl benzyl chloride (hereinafter (VBC)),VBC/styrene/divinylbenzene (hereinafter DVB), butadiene/styrene/VBC,VBC/butadiene/acrylonitrile, acrylonitrile/styrene/VBC and isoprene/VBC.The identified polymers are not intended to be an exhaustive list ofuseful polymers. This disclosure is intended to include other polymersthat have a pendant vinyl group. These polymers are known to one ofordinary skill in the art.

The polymer having a pendant vinyl group and the functionalizedthioester are combined in the desired stoichiometric ratio to allow thedesired amount of functionalization of the polymer to occur. In oneembodiment of the invention, the amount of pendant vinylgroup:functionalized thioester ranges from 0.1 to 100 mol/mol ratio. Inone embodiment of the invention, the amount of pendant vinylgroup:functionalized thioester ranges from 0.01 to 100 mol/mol ratio. Inone embodiment of the invention, the amount of pendant vinylgroup:functionalized thioester ranges from 0.5-1.5 mol/mol ratio. Thestoichiometric amount is selected based on the desired C═C/SH molarratio.

In an embodiment, the reactions described here are carried out at asuitable temperature as easily determined by one of ordinary skill inthe art without undue experimentation. In an embodiment, a reaction iscarried out at a temperature selected over the range of 10 degreesCelsius to 150 degrees Celsius. In embodiments, useful solvents for themethods described herein include: a dimethoxyethane solvent, an ether, ahalogenated solvent, or an aromatic solvent. In embodiments, usefulsolvents for the methods described herein include dimethoxyethane,tetrahydrofuran, chloroform, toluene, benzene, ethylbenzene, xylenes,tetrachloroethane, methanol:THF, or methanol:chloroform. In embodiments,the solvent is 20:80 methanol:THF. In embodiments, the solvent is 20:80methanol:chloroform. As known in the art, mixtures of solvents may beused. Such mixtures are included in the disclosure herein, and areeasily determined by one of ordinary skill in the art without undueexperimentation.

In an embodiment, the functional group is selected from the groupconsisting of: amino acid, peptide, polypeptide, nucleic acid, lipid,carbohydrate, carbazole, benzoate, phenol, pyridine, cyanobiphenyl,perfluorocarbon, polyethylene oxide (PEO) and polypropyleneoxide (PPO)groups. In embodiments, small (i.e. MW 500 to 5000) polyethylene oxide(PEO) or polypropyleneoxide (PPO) groups are used. The functional groupsspecifically identified herein are not intended to be limiting. Thisdisclosure is intended to include other desired functional groups thatcan be used in the methods of the invention without undueexperimentation.

In an embodiment, the reaction of the polymer with the functional thiolis initiated by a free-radical initiator. Any suitable initiator/methodof initiation may be used, including thermal activation and lightactivation (such as using UV light). When light, particularly UV light,is used for the reaction, a photoinitiator may be required, as known inthe art. Initiators and their use are known in the art. In embodiments,the initiator is chosen from 2,2-azobisisobutyronitrile (AIBN), benzoylperoxide (BPO), diisopropyl peroxydicarbonate (IPP),t-butylhydroperoxide (TBPO), heat-activated initiators, andlight-activated initiators such as camphorquinone (Aldrich),4-(2-hydroxyethoxy)-phenyl-(2-hydroxy-2-methylpropyl)ketone (Irgacure2959, Ciba-Geigy) and mixtures thereof. The amount of initiator used iswell known in the art, is chosen for a given reaction temperature toachieve a target rate of initiation, and is typically 0.1% to 20% molarequivalent of the reactants involved in the radical reactions.

Also provided in an embodiment is a method of preparing a functionalizedthioester comprising: (a) reacting a starting material having a desiredfunctional group with a nonsymmetrical bifunctional linker molecule,forming a functionalized intermediate and (b) reacting thefunctionalized intermediate with a thiol acid to form a functionalizedthioester. As used herein, “functionalized thioester” is intended to bea protected thiol. In an embodiment, the starting material is anucleophile. In an embodiment, the starting material is an electrophile.

In embodiments, the method of preparing a functionalized thioester cantake a variety of forms. Although Applicant does not wish to be bound bytheory, the following nonlimiting examples are provided. In oneembodiment, a nucleophilic substitution reaction of a nucleophile havinga desired functional group with a nonsymmetrical bifunctional linkermolecule having two leaving groups (such as ClCH₂CH₂OTs) is followed byreaction with a thiol acid to form the functionalized thioester (i.e., aprotected thiol). “Ts” stands for the tosyl group. In one embodiment, anucleophilic substitution reaction of a nucleophile having a desiredfunctional group with a nonsymmetrical bifunctional linker moleculehaving one leaving group (such as a chloroalcohol, for exampleH(OCH₂CH₂)_(n)Cl, where n is an integer from 1 to 10, for example) isfollowed by conversion of the linker's other functional group into aleaving group (e.g. in the example of a chloroalcohol as the linker,conversion of the hydroxyl group into a tosylate or other leavinggroup), followed by reaction with a thiol acid to form thefunctionalized thioester. This reaction allows the use of harsherconditions for the first step, and is a convenient way to incorporatelinkers of different lengths. In one embodiment, esterifying acarboxylic acid nucleophilic starting material with a chloroalcoholnonsymmetrical bifunctional linker molecule, followed by reaction with athiol acid is used to form the functionalized thioester. In oneembodiment, reacting a nucleophilic starting material having a desiredfunctional group with allyl bromide followed by a radical reaction witha thioacid is used to form the functionalized thioester.

As used herein, a “nonsymmetrical bifunctional linker molecule” containstwo different functional groups: one functional group binds to thestarting material functional group and the other functional group bindsto a thiol group. As used herein, “binds” generally indicates covalentbonding between two moieties.

The thiol acid (also referred to as thioacid) used can be any thiolacid. In embodiments, the thiol acid is thiobenzoic acid or thioaceticacid. In embodiments, the nucleophilic starting material is a carboxylicacid, an alcohol, an amine, a phenol, or a heterocyclic nitrogencompound. In embodiments, the bifunctional linker molecule is achloroalcohol or allylbromide. In embodiments, the bifunctional linkermolecule is a Cl CH₂CH₂OTs or H(OCH₂CH₂)_(n)Cl, where n is an integerfrom 1 to 10, for example. In embodiments, the bifunctional linkermolecule is any molecule which is capable of linking a nucleophilicstarting material with a thioacid.

In an embodiment, the protecting group for the thiol moiety is an acetylor benzoyl group. The protecting groups listed specifically are notintended to be limiting, and other suitable protecting groups may beused.

In embodiments, the functional group is selected from those functionalgroups described above. In embodiments, the solvent for the first stepin the reactions is DMSO, although other solvents may be used, as knownin the art including those suitable solvents and solvent mixturesdescribed elsewhere herein.

Also provided is a functionalized thioester made by the methodsdescribed herein. Also provided is a functionalized polymeric materialmade by the methods described herein.

Also provided is a functionalized thioester having the followingformula:

wherein R is a functional group and COR′ is a protecting group that isreadily cleaved to provide a functional thiol that may be used withoutisolation to perform thiol-ene coupling. The functional groups andprotecting groups can be selected from those groups described herein.

Also provided is a method of making a functionalized molecule using athiol-ene reaction comprising:

providing a functionalized thioester having the following formula:

wherein R is a functional group and COR′ is a protecting group; cleavingthe functionalized thioester, forming a functional thiol and an acylgroup;

providing a molecule having a pendant vinyl group; reacting the moleculewith the functional thiol whereby a functionalized molecule is formed,wherein the functional thiol is not isolated prior to reacting with themolecule. The molecule can be any molecule having a pendant vinyl group,including small molecules and fine chemicals.

All reactions are carried out under suitable reaction conditions asknown in the art. Suitable reaction conditions include temperature,time, solvent(s) and other aspects of organic synthesis that one ofordinary skill in the art is easily able to determine without undueexperimentation using the description provided herein and the knowledgeof one of ordinary skill in the art. For example, the thiol-ene radicalreaction temperature is any suitable temperature, such as between 10° to150° C., depending on the type of initiator used.

It will be appreciated that the groups specifically identified in theprotected functionalized thioester moiety may be connected to each otherwith a suitable linker or other group, as known in the art. For example,the functional group may be connected to the thioester group with one ormore atoms or groups. Also the carbon of the thioester group may beconnected to the protecting group with one or more atoms or groups, forexample methylene linkers. For example, optionally substituted alkyl,benzyl, or aryl groups can be used including linear or branched alkylgroups, cyclic aromatic or non-aromatic, heterocyclic aromatic ornon-aromatic structures, all of which may be optionally substituted withone or more of the same or different substituents. The optionalsubstituents include one or more of electron donating or electrondonating groups, such as heteroatoms in the chain or attached to thechain, carbonyl, nitrile, sulfoxy, sulfone, sulfate, halogen, C1-C6linear or branched alkyl groups, benzyl, benzyl groups, ketone, ester,amino, nitro, I, Br, Cl, F, and other groups which are known in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a ¹H NMR trace of unfunctionalized polymer 92 kg/mol 1,2-PB.

FIG. 2 is a ¹H NMR trace of functionalized 1,2-PB polymer 92 kPB-OH(experimental conditions are given in Table 2).

FIG. 3 is a ¹H NMR trace of functionalized 1,2 PB polymer 92 kPB-DNB(experimental conditions are given in Table 2).

FIG. 4 is a ¹H NMR trace of functionalized 1,2 PB polymer 820 kPB8(experimental conditions are given in Table 1).

FIG. 5 is a ¹H NMR trace of functionalized 1,2 PB polymer 92 kPB6(experimental conditions are given in Table 1).

FIG. 6 is a ¹H NMR trace of functionalized 1,2 PB polymer 820 kPB12(experimental conditions are given in Table 1).

FIG. 7 is representative ¹H NMR spectra of functionalized1,2-polybutadiene polymers (92 kPB13, top trace, and 92 kPB3, bottomtrace; refer to Table 1). Note that the two protons of the RCH₂SCH₂—methylene groups directly attached to ring structures are not equivalentand hence give separate signals. In both spectra, visible peaks at δ=6.97, 2.27, and 1.43 ppm belong to 2,6-ditert-butyl-4-methylphenol(BHT), and peaks near δ=1.6 ppm correspond to water.

FIG. 8 shows representative solid-state ¹³C NMR spectrum offunctionalized 1,2-polybutadiene polymer (92 kPB3; refer to Table 1 andto structure at bottom of FIG. 7).

FIG. 9 shows representative gel permeation chromatography trace offunctionalized 1,2-polybutadiene (1,2-PB) polymer. The solid linecorresponds to 92 kPB3 (refer to Table 1); the dashed line is 92 kg/mol1,2-PB polymer.

FIG. 10 shows the fraction p₁ of species I (Scheme 4) to proceed toabstract hydrogen from RSH as a function of [RSH] exhibits a linearincrease at low concentration and saturates above a characteristicconcentration that corresponds to p₁/(p₂+p₃)≈10.

FIG. 11 shows crosslinking (left) and chain scission (right): gelpermeation chromatography traces of 1,2-polybutadiene functionalized byreaction in the presence of dibenzoyl disulfide (solid line, left, 92kPB16), and in a one pot synthesis after deprotection of triphenylmethylsulfide derivatives (solid line, right, 820 kPB14). The dashed linescorrespond to polymer starting materials.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the broadest meanings as commonly understood by one of ordinaryskill in the art to which this invention pertains. In addition, herein,the following definitions apply:

Alkyl groups include straight-chain, branched and cyclic alkyl groups.Alkyl groups include those having from 1 to 30 carbon atoms. Alkylgroups include small alkyl groups having 1 to 3 carbon atoms. Alkylgroups include medium length alkyl groups having from 4-10 carbon atoms.Alkyl groups include long alkyl groups having more than 10 carbon atoms,particularly those having 10-30 carbon atoms. Cyclic alkyl groupsinclude those having one or more rings. Cyclic alkyl groups includethose having a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-member carbon ring andparticularly those having a 3-, 4-, 5-, 6-, or 7-member ring. The carbonrings in cyclic alkyl groups can also carry alkyl groups. Cyclic alkylgroups can include bicyclic and tricyclic alkyl groups. Alkyl groups areoptionally substituted. Substituted alkyl groups include among othersthose which are substituted with aryl groups, which in turn can beoptionally substituted. Specific alkyl groups include methyl, ethyl,n-propyl, iso-propyl, cyclopropyl, n-butyl, s-butyl, t-butyl,cyclobutyl, n-pentyl, branched-pentyl, cyclopentyl, n-hexyl, branchedhexyl, and cyclohexyl groups, all of which are optionally substituted.Substituted alkyl groups include fully halogenated or semihalogenatedalkyl groups, such as alkyl groups having one or more hydrogens replacedwith one or more fluorine atoms, chlorine atoms, bromine atoms and/oriodine atoms. Substituted alkyl groups include fully fluorinated orsemifluorinated alkyl groups, such as alkyl groups having one or morehydrogens replaced with one or more fluorine atoms. An alkoxyl group isan alkyl group linked to oxygen and can be represented by the formulaR-0.

Alkenyl groups include straight-chain, branched and cyclic alkenylgroups. Alkenyl groups include those having 1, 2 or more double bondsand those in which two or more of the double bonds are conjugated doublebonds. Alkenyl groups include those having from 2 to 20 carbon atoms.Alkenyl groups include small alkenyl groups having 2 to 3 carbon atoms.Alkenyl groups include medium length alkenyl groups having from 4-10carbon atoms. Alkenyl groups include long alkenyl groups having morethan 10 carbon atoms, particularly those having 10-20 carbon atoms.Cyclic alkenyl groups include those having one or more rings. Cyclicalkenyl groups include those in which a double bond is in the ring or inan alkenyl group attached to a ring. Cyclic alkenyl groups include thosehaving a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-member carbon ring andparticularly those having a 3-, 4-, 5-, 6- or 7-member ring. The carbonrings in cyclic alkenyl groups can also carry alkyl groups. Cyclicalkenyl groups can include bicyclic and tricyclic alkyl groups. Alkenylgroups are optionally substituted. Substituted alkenyl groups includeamong others those which are substituted with alkyl or aryl groups,which groups in turn can be optionally substituted. Specific alkenylgroups include ethenyl, prop-1-enyl, prop-2-enyl, cycloprop-1-enyl,but-1-enyl, but-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, pent-1-enyl,pent-2-enyl, branched pentenyl, cyclopent-1-enyl, hex-1-enyl, branchedhexenyl, cyclohexenyl, all of which are optionally substituted.Substituted alkenyl groups include fully halogenated or semihalogenatedalkenyl groups, such as alkenyl groups having one or more hydrogensreplaced with one or more fluorine atoms, chlorine atoms, bromine atomsand/or iodine atoms. Substituted alkenyl groups include fullyfluorinated or semifluorinated alkenyl groups, such as alkenyl groupshaving one or more hydrogens replaced with one or more fluorine atoms.

Aryl groups include groups having one or more 5- or 6-member aromatic orheteroaromatic rings. Aryl groups can contain one or more fused aromaticrings. Heteroaromatic rings can include one or more N, O, or S atoms inthe ring. Heteroaromatic rings can include those with one, two or threeN, those with one or two 0, and those with one or two S, or combinationsof one or two or three N, O or S. Aryl groups are optionallysubstituted. Substituted aryl groups include among others those whichare substituted with alkyl or alkenyl groups, which groups in turn canbe optionally substituted. Specific aryl groups include phenyl groups,biphenyl groups, pyridinyl groups, and naphthyl groups, all of which areoptionally substituted. Substituted aryl groups include fullyhalogenated or semihalogenated aryl groups, such as aryl groups havingone or more hydrogens replaced with one or more fluorine atoms, chlorineatoms, bromine atoms and/or iodine atoms. Substituted aryl groupsinclude fully fluorinated or semifluorinated aryl groups, such as arylgroups having one or more hydrogens replaced with one or more fluorineatoms.

Polymers are molecules or nanoparticles comprising multiple repeatingunits, including but not limited to synthetic homopolymers, copolymersand block copolymers; oligopeptides, polypeptides and proteins;oligonucleotides and polynucleotides; oligosaccharides andpolysaccharides; hyperbranched molecules and dendrimers; latex particlesand organic/inorganic particles and inorganic particles bearing organicfunctional groups on their surfaces. It is understood that the methodsof the invention may be applied to cross linked polymers and to polymersattached to surfaces or in pores. When applied to immobilized polymers,it is understood that the methods of the invention can be applied in aspatially resolved manner by using spatially-resolved generation ofradicals.

The invention will now be illustrated by way of example only and withreference to the following non-limiting examples and experiments.

There are several known protecting groups for thiols that can be used inthe present invention. For example, see Wuts, P. G. M., Greene'sProtective Groups in Organic Synthesis/Peter G. M. Wuts and Theodora W.Greene. 4th ed.; Wiley-Interscience: 2007; ch 6; and Kocienski, P. J.,Protecting Groups. 3rd ed.; Thieme: 2004; ch 5.

The methods described here can be used for grafting variousfunctionalities in a one-step polymer reaction (as opposed tohydroboration or epoxidation). Thiol-ene coupling described hereproceeds under mild reaction conditions and is tolerant of a largenumber of functional groups. In particular, the chemistry is waterinsensitive, which renders it considerably simpler than hydrosilylation,for instance. The thiol addition described here also proceeds withminimal cross-linking or chain scission in comparison to othermodification reactions such as hydroboration/oxidation¹³ andhydrosilylation^(23,24). Finally, desired side-groups are incorporatedvia unobtrusive thioether linkages, without the introduction ofadditional functionalities (in contrast to functionalization byepoxidation or radical addition of alkyl iodides, which add one molarequivalent of hydroxyl, chloro, or iodo functionalities per grafted sidegroup).

Thiol-ene addition to PB and other polymers having pendant vinyl groupsoffers tremendous versatility for molecular design. The excellenttolerance of thiol-ene coupling to numerous functional groups combineswith the good availability of polymers of well-defined microstructures(e.g., content of 1,2-adducts in PB), macromolecular structure (such aschain topology and incorporation of other polymer blocks), and size(from <10⁴ g/mol to >10⁶ g/mol). If desired, a polymer having pendantvinyl groups can be synthesized according to known methods. The methodis well suited to produce a homologous series of model materials (i.e.,having precisely matched degree of polymerization, but varying infunctionality and/or in extents of functionalization) that elucidatemacromolecular physical phenomena.

The main drawback to currently available thiol-ene reactions is thelimited range of commercially available mercaptans (essentially limitedto carboxylic acid, alcohol, 1,2-diol, amine, alkyl, and fluoroalkylfunctionalities). Therefore, the rapid, high-yield synthetic methods toprepare desired functional thiols described herein are needed to makethiol-ene functionalization widely useful. Furthermore, technologicalapplication requires that these synthetic methods be amenable to scaleup. Indirect preparation of thiols through thioester intermediates asdescribed herein presents significant advantages with regard to safety,yield, and product stability. Facile procedures to deprotect the thiolsand—without isolation—proceed to functionalize 1,2-PB are described(e.g., Scheme 1). Thus, this invention shows how to conveniently extendthe number of candidate side-groups for functionalization of polymers bythiol-ene coupling.

Exemplified herein are highly efficient synthetic routes to an array ofprotected thiols which were chosen both i) because the featuredside-groups are important functionalities in their own right, and ii)because each is representative of a general pathway for incorporation ofthe thiol moiety (e.g., Scheme 2). Specifically, phenol and pyridinefunctionalities are described because of their relevance ashydrogen-bond donor and acceptor; carbazole and dinitrobenzoate are ofinterest as electron donor and acceptor, and relevant to materials withnovel electronic properties; and 4-cyano-4′-hydroxybiphenyl is ofinterest for its liquid-crystalline properties. Of paramount practicalsignificance, the described chemistry involves: i) inexpensive, readilyavailable reagents of moderate toxicity and reactivity, ii) no elaborateequipment or procedures, iii) rapid, quantitative conversions oflimiting reagents in all steps without measurable formation ofside-products, and iv) simple purification (enabled by the cleansynthetic routes) using scalable separation processes (principallyliquid-liquid extraction and washes, occasionally recrystallization, butno column separations).

The set of protected thiols exemplified here was chosen to illustrateclean, high-yield synthetic routes to introduce the thiol moiety ontofunctional molecules. Molecules were selected for the importance oftheir functionalities and for their reactive groups available forderivatization (Scheme 2). Thus, the synthesis of protected mercaptansusing an accessible phenol or alcohol group (compounds 3 and 6), aheterocyclic nitrogen atom (compound 8), an accessible carboxylic acidgroup (compounds 10 and 12), a terminal olefin group (compound 10), oran available halide atom (compounds 3, 8, 12, and 13) are provided asexamples. Compounds 3 and 6 illustrate convenient methods to control thedistance between the grafted side-group and the polymer backbone afterthiol-ene coupling. Note that an 8 atom spacer (or other size) can beincorporated by replacing H(OCH₂CH₂)₂Cl with commercially availableH(OCH₂CH₂)₃Cl or analogs in the described procedure for the synthesis of4.

Reaction conditions for the synthesis of compounds 2-13 demonstratehighly efficient and scalable methods that can be generalized to thepreparation of related compounds (in terms of the reactive groupsavailable for derivatization). ¹H NMR analysis of crude reactionmixtures showed that all reaction steps resulted in quantitativeconversion to desired product (except synthesis of 9 and 11, for whichconversion was ˜90%). The clean synthetic steps made it possible toisolate products in 95-100% purity and 90-100% yield by mere use ofliquid-liquid extraction/washes, and evaporation of low-boilingcompounds. In some cases, further purification was achieved byrecrystallization to yield analytically pure product (compounds 3, 7, 8,and 12).

Functionalization of 1,2-PB. Reaction conditions for 1,2-PBfunctionalization given in Table 1 incorporate functional side-groupswhile preserving the narrow molar mass distribution of theunfunctionalized polymer material (Table 1, Scheme 3, FIGS. 7-9).Depending on the application, degrees of functionalization from s≦1% to≧50% are of interest; here, systematic control of functionalization(X_(funct)) from a few % to 40% is demonstrate d (Table 1). PB chainswith very high 1,2-content tend to form cyclic adducts, which limitfunctionalization to ≦50% unless very high thiol concentrations areused.^(18,19) Accounting for the formation of ring structures by randomcyclization of adjacent repeat units during the addition reaction, thegeneral structure of the functionalized polymer is as shown in Scheme 3.That structure is solved by considering that either five- or six-memberrings can be formed, and that polycyclic structures are possible. Notethat any cyclic or polycyclic structure involves at most one five memberring (on either side of which can be fused any number of six-memberrings), and that there are exactly as many methyl groups in thefunctionalized polymer as there are five-member rings. Let X_(funct) bethe fraction of reacted 1,2-PB repeat units bearing functional groups,X_(unreact) be the fraction of unreacted 1,2-PB repeat units, andX_(cycl) be the fraction of reacted 1,2-PB repeat units that areunfunctionalized. Thankfully, analysis of the general structure (FIG. 7)provides an unambiguous relationship between X_(funct), X_(unreact),X_(cycl) and three quantities that are readily determined from the ¹HNMR spectra: the relative values of the integrals of RCH₂S— methyleneprotons (S₁), H₂C═CH— alkenic protons (S₂), and aliphatic protons ofchemical shifts below 2.2 ppm (S₃). In terms of the indices defined inFIG. 1, S₁˜2 (n+m+m′) and S₂˜2 u. Furthermore, since none of theside-groups R in the present study display protons with δ<2.2 ppm, S₃˜[5n+4 (m+m′)+6 (p+p′+t)+7 (q+v)+3 u]. Because there are as many beginningsas ends in both y and z structures (Scheme 3, top), m=q, and m′=v;therefore, (p+p′+t+q+v)=(2S₃−3 S₂−5 S₁)/12. Thus, X_(funct),X_(unreact), and X_(cycl) can be calculated by the expressions belowwithout any knowledge of the relative amounts of the repeat units m, m′,p, p′, q, t, or v in the functionalized polymer:

$X_{funct} = {\frac{n + m + m^{\prime}}{n + m + m^{\prime} + p + p^{\prime} + t + q + v + u} = \frac{6S_{1}}{S_{1} + {3S_{2}} + {2S_{3}}}}$$X_{unreact} = {\frac{u}{n + m + m^{\prime} + p + p^{\prime} + t + q + v + u} = \frac{6S_{2}}{S_{1} + {3S_{2}} + {2S_{3}}}}$X_(cycl) = 1 − X_(funct) − X_(unreact)

Functional polymer could also be obtained in a two-step polymermodification procedure, by thiol-ene addition of β-mercaptoethanol(BME), followed by esterification of the incorporated hydroxyl groupswith a suitable acyl halide (Scheme 4, Table 2). The narrowpolydispersity of well-defined polymer material could also be preservedthroughout this process (Table 2), so that the procedure offers a usefulalternative to direct coupling of a thiol derivative when an acylchloride compound featuring the desired functionality is readilyaccessible.

Molecular Structure of Functionalized 1,2-PB Polymer. The potential toform cyclic structures follows from the reaction mechanism. The additionreaction is initiated by abstraction of a thiol hydrogen by acyanopropyl free radical. The resultant thiyl radical (RS•) adds to adouble bond of 1,2-PB in anti-Markovnikov fashion¹⁶⁻¹⁸, generating apolymeric alkyl radical (e.g. Structure I in Scheme 3). As shown in thefigure, transfer of hydrogen from another thiol molecule completes theaddition reaction (Structure II) and regenerates a new RS• participant;alternatively, intramolecular reactions of I compete with hydrogentransfer to form Structures III and IV. As evidence for the formation ofring structures by intramolecular cyclization, Schlaad^(18,19) pointedto incomplete functionalization at full conversion of double bonds using1,2-PB-block-poly(ethylene oxide) as starting material, i.e. typicallyonly 60-80 functional side-group were found for every 100 reacted 1,2-PBrepeat units. Direct evidence of cyclization is seen in the ¹H NMRspectra in the present study (bottom trace in FIG. 7 and FIG. 1-6): thebroad peaks below 2.2 ppm are not consistent with the structures ofrepeat units w and x in Scheme 3, but consistent with cyclohexyl orcyclopentyl proton signals. Further, the observed multiple peaksassignable to the RCH₂SCH₂— protons of the functionalized polymer(protons 4, 5, 6, FIG. 7) cannot be explained in the absence ofcyclization, but are consistent with a combination of the repeat unitsn, m, and m′ in Scheme 3.

The question now arises whether radical I in Scheme 4 predominantlyforms III or IV during cyclization. Based on the relative thermodynamicstability of secondary versus primary radical intermediates, Schlaad andcoworkers¹⁸ have suggested that six-member rings (III) should bepreferred over their five-member counterparts (IV); however,experimental results discussed in the next few paragraphs give insteadevidence to the contrary. First, the data presented here reveals a highcontent of five-member rings in reacted polymer. NMR analysis of ourproduct for highly functionalized chains shows i) a strong peak around17 ppm in the solid state ¹³C spectra (FIG. 8), and ii) a strong signalat 1-0.9 ppm in the ¹H NMR spectra (FIG. 7, bottom). Both these signalsare consistent with the methyl group of structure v in Scheme 5. Sincethere are exactly as many five-member rings as methyl groups in thefunctionalized polymer, it is deduced that a large number ofunfunctionalized, reacted monomers cyclized into five-member rings.

Next, literature results^(22,30) on the radical addition of primaryalkyl iodides to 1,2-PB and α,ω-alkadienes provides further evidence.Although the initiation, addition, and transfer steps for RI versus RSHradical addition involve molecules of substantially differentreactivity, the intermediate radicals involved in intramolecularcyclization have essentially the same structure (i.e. replace RS by R instructures I, III, and IV of Scheme 5). Thus, the relative rates offormation of five- versus six-member ring structures should becomparable. According to reports on the radical addition ofperfluoroalkyl iodides to 1,2-PB²² and 1,6 heptadiene³⁰, intramolecularreaction of polymer radical I is expected to form primarily five-,instead of six-, member cyclic intermediates (structure IV rather thanIII).

In order to make further progress, let us now inquire about thecompetition between H-abstraction by I (forming II) versus cyclizationof I (to form III or IV). This competition depends both on thiolconcentration and steric hindrance to H-abstraction by I. Let r₁, r₂, r₃and p₁, p₂, p₃ be the reaction rates and transitional probabilities forthe pathways I II, III, or IV, respectively (Scheme 4). At low extentsof conversion, steric hindrance to H-abstraction by I is small, so thatp₁/(p₂+p₃)=r₁/(r₂+r₃)˜[RSH]. Schlaad's date demonstrated that atsufficiently high [RSH] (on the order of 10 M), H-abstraction waspredominant, and degrees of functionalization as high as X_(funct)=85%could be obtained. Only marginal increases in X_(funct) could beachieved with increasing [RSH] above 10 M, but Schlaad observed thatcyclization began to compete noticeably at [RSH]≦5 M. It is now shownthat these observations indicate that p₁/(p₂+p₃)˜10 at 5 M RSH. At lowextents of reactions, p₁(p₂+p₃)=p₁/(1−p₁) is proportional to [RSH]. Theproportionality constant pertinent to low extents of conversion isdenoted by k, i.e. p₁/(p₂+p₃)=k[RSH], giving p₁=k[RSH]/(1+k[RSH]). Atvery high thiol concentrations (k[RSH]>>1 in FIG. 10), p₁=1 and p₂=p₃=0,so that there is no cyclization. Upon decreasing [RSH], cyclizationbegins to compete noticeably. The onset of competition as seen in FIG.10 occurs at k[RSH]=p₁/(p₂+p₃)˜10, where p₁≈0.9.

The above result has important implications for the relative formationof five-vs. six-member rings. First, the finding that k˜O(1 M⁻¹) leadsimmediately to the realization that under the functionalizationconditions used in the present study ([RSH]˜O(10⁻¹ M or less), radical I(FIG. 5) primarily undergoes intramolecular reaction, i.e.p₁≈p₁/(p₂+p₃)˜O(10⁻¹ or less). Second, the fact that very little ofradical I proceeds to abstract H from RSH under these conditionssuggests that likewise very little of radical III would abstract H underthe same conditions (judging reactivity based on structure similarity).Therefore, if, as Schlaad suggests, intramolecular cyclization of I ledprimarily to the six-member rings III, the similarity of I and III wouldcause III to propagate a ladder of many six-member cycles prior toconcluding with H-abstraction from RSH. In that case, the functionalizedpolymer here would then display i) very high ratios of cyclization tofunctionalization, X_(cycl)/X_(funct)>>1, and ii) very few five-memberrings. Both these results are contrary to the observations.

The data is consistent with the following predominant pathway: I→IV→V(Scheme 4) for thiol concentrations on the order of 10⁻²-10⁻¹ M. Thatis, I cyclizes predominantly, and five-member rings are more likely, butIV abstracts hydrogen predominantly. Note that such different relativereactivity for radicals I and IV are reasonable based on theirstructures. Further, this reaction pathway successfully explains theobserved ratios of X_(funct)/X_(cycl) in the relatively narrow range of0.65-1 (Tables 1 and 2) over the >1 order of magnitude range of thiolconcentration spanned by our experiments. If the reaction proceededexclusively from Ito IV to V (p₁=p₂=p₅=0), then X_(funct)/X_(cycl)=1 andthe polymer structure would consist exclusively of unreacted 1,2 unitsand functionalized five-member rings. In reality, deviations from p₂=0or p₅=0 account for values of X_(funct)/X_(cycl) smaller than 1, anddeviation from p₁=0 account for values of X_(funct)/X_(cycl) largerthan 1. Increasing [RSH] increases p₁, leading to a greater number ofacyclic functionalized units. The general predominant polymer structureis therefore the one given in Scheme 1.

Direct or Indirect Functionalization? The utility of indirectfunctionalization by esterification of 2-hydroxyethylthio-modified PB(Scheme 4) is somewhat limited by the high reactivity of acyl halides,which renders them incompatible with a number of important functionalgroups and working conditions. Furthermore, our experience with polymersthat are susceptible to cross-linking (such as high MW 1,2-PB) indicatesthat best results are typically achieved by minimizing the number ofsynthetic steps involving macromolecules. Finally, the time invested inthe synthesis of protected thiols is easily regained in subsequenttailoring of polymer properties by quicker adjustments in the numberdensity of grafted side-groups. Thus, in the research reported here, itis seen that direct polymer functionalization according to Scheme 1 ispreferable in most cases. However, indirect functionalization accordingto Scheme 4 becomes useful when i) a suitable acyl halide iscommercially available, and/or ii) Scheme 1 fails for one reason oranother; e.g. due to unsatisfactory deprotection of a suitable thiol.For instance, deprotection of compound 10 to give the correspondingmercaptan did not give acceptable results due to apparent partialreduction of the nitro groups.

Choice of Protecting Group. The motivation for using protected thiolsarises from issues of safety, yield, efficiency, and product stability.Direct preparation of thiols can be achieved by addition of hydrogensulfide (H₂S) to alkenes, or by substitution of alkyl halides withhydrogen sulfide or hydrosulfide (HS⁻). These methods have the followingdisadvantages: first, both hydrogen sulfide and hydrosulfide presentconsiderable health hazards, and second, sulfide byproducts are usuallyformed in significant amounts^(27,31). Alternatively, the thiolfunctionality can be incorporated indirectly using othersulfur-containing compounds such as thiolcarboxylic acids, thiourea, orthe thiolsulphate ion, followed by bond cleavage via e.g. hydrolysis ofthe intermediates to generate the desired mercaptan³¹. The extra steprequired by any indirect method is balanced by the advantages ofcleaner, less wasteful reactions, and the use of less toxic reagents.Because thiols are prone to oxidation (e.g. in air on standing), storageof protected thiols is also often considered a wiser choice.

Based on adverse side reactions that occur with the triphenylmethyl(trityl) group, it was necessary to turn to other protecting groups. Thewidespread use of the trityl grouP³² reflects the ease by which it isfirst incorporated by substitution of halides using triphenylmethylmercaptan, and the ease with which it is quantitatively removed (<2hours in DCM at room temperature in the presence of TFA and triethyl- ortriisopropylsilane³³⁻³⁶). The current interest in the trityl sulfidegroup was generated by the hope that both deprotection of the sulfideand addition of the resultant thiol to PB could be successfully carriedout in one pot by using chloroform as the solvent (procedure describedbelow). Unfortunately, experiments with9-[2-(triphenylmethyl)thio]ethyl]carbazole (14) showed that althoughboth deprotection and addition reactions proceeded as desired,unacceptable degradation of the polymer also occurred under suchconditions (FIG. 11, right). It is also worth noting thattriphenylmethyl mercaptan is a comparatively expensive reagent for theintroduction of the thiol functionality.

Thioesters have been used extensively in the past as protecting groupsof the thiol functionality, with more or less success towards selectivedeprotection based on the reagents and method used³⁷. In saccharidesynthesis, thioester groups have been reported to be removed under mildconditions, i.e. in <2 hours at room temperature hydrazine acetate inDMF³⁸⁻⁴⁰. Oxygen esters were reported to be resistant to hydrolysisunder these conditions. In this work, it was found that thioacetic acidand thiobenzoic acid were essentially equivalent in reactivity, but thatthiobenzoic acid offers the advantage of simpler purification of thethioester product due to differences in both solubility and meltingpoint between products and impurities. For instance, the highermolecular weight products obtained with PhCOSH were usually solidcompounds amenable to recrystallization.

Synthetic Crossroads for the Introduction of the ThioesterFunctionality. Thioesters can be generated using thioacetic acid orthiobenzoic acid either from nucleophilic displacement of a leavinggroup or from radical addition to a terminal alkene (Scheme 2). Reactionof a halide or tosylate is considerably more convenient than reaction ofan alkene, since the nucleophilic displacement i) does not requireoxygen free conditions, and ii) essentially does not generate anyimpurities. Indeed, quantitative radical reaction of alkenes (e.g.synthesis of 10) is accompanied by the formation of radical terminationproducts (0.05 to 0.3 molar equivalent) which can greatly complicate thepurification process.

In some cases a leaving group (e.g. synthesis of 13) or alkene may bedirectly available, otherwise they can be introduced in one of thefollowing ways: i) alcohols can be converted into good leaving groups bytosylation (e.g. synthesis of 5), ii) carboxylic acids can be reacted byFisher esterification with e.g. 2-chloroethanol (e.g. synthesis of 11),and iii) nucleophiles can be alkylated with, for instance, allyl bromide(e.g. synthesis of 9) or 2-chloroethyl-p-toluenesulfonate (compound 1,e.g. synthesis of 2 or 7). The following considerations affect decisionmaking regarding alkylation of nucleophiles. On the one hand, allylbromide is considerably more reactive and available than 1, and itsreaction with nucleophiles proceeds cleanly (in contrast, care must betaken in choosing reaction conditions with compound 1 to preventbisubstitution and minimize elimination). On the other hand, the use ofallyl bromide suffers in the conversion of the resulting alkene to thedesired protected thiol (e.g., 9 to 10). As noted earlier, that reactionis air sensitive, and the side-products are often difficult to separatefrom the desired one. As a result, the ease of conversion andpurification of thioesters from halides (e.g., 3 from 2) often justifythe additional care required in the coupling of 1 to the molecule ofinterest (e.g. 1 to 2).

Functional precursors bearing nucleophilic atoms also afford aconvenient method to control the spacer length between the functionalgroup of interest and the polymer backbone. For instance, 3, 5 and 8atom spacers can be accessed by alkylation of a nucleophile withinexpensively available H(OCH₂CH₂)_(n)Cl (n=1,2,3; Wako Chemicals),followed by conversion to a protected thiol as in the synthesis of 6.

Deprotection of acetyl- or benzoyl-thioesters. In all cases (with theexception of compound 10), cleavage of thioesters was achieved in >95%yields (verified by ¹H NMR analysis) in 2-4 hours with hydrazine acetatein DMF at room temperature (Scheme 1, step 1.1). Significantly, it wasdiscovered that hydrazine acetate could be generated in situ by ionexchange in DMF from considerably less expensive hydrazine hydrochlorideand sodium acetate, with equally successful results.

A most compelling advantage of Scheme 1 for functionalization of PBusing acetyl- or benzoyl-thioesters consists in the direct addition ofthe deprotected mercaptan to PB without its isolation as a purifiedintermediate. Extraction of the DMF reaction mixture with chloroform orDCM and subsequent washing of the organic phase (Scheme 1, step 1.2)yields in ˜30 min a remarkably pure solution of the thiol in which theonly impurities are small amounts of disulfide (due to exposure to air),unreacted thioester (<5% of initial amount), DMF, and moisture. Radicaladdition of the thiol to PB is highly tolerant of these impurities andproceeds unaffected by their presence (Table 1).

Effect of Impurities. The radical addition of mercaptans to alkenes isknown to be highly tolerant of a vast array of functional groups²⁷.Indeed, it was found that most impurities (such as disulfides,thioesters, solvents, water, etc.) were inconsequential during thiol-enefunctionalization of PB, with the following notable exceptions. First,in one-pot reaction procedures after detritylation of triphenylmethylsulfides, some unidentified compound(s) caused chain scission of 1,2-PB(as mentioned earlier, FIG. 11, right). Second, it was found that thepresence of benzoyl disulfide (PhCOSSOCPh) resulted in significantcross-linking. For example, use of a sample of thiobenzoic acidS-[3-(9-carbazolyl)propyl]ester (16) containing ˜0.2 molar equivalent ofbenzoyl disulfide caused polydispersity to increase from PDI=1.07 to1.34 at 19% functionalization (FIG. 7, left).

Implications of Extents of Cyclization for 1,2-PB. Depending on thereason for modifying the polymer, degrees of functionalization from afew % up to ˜100% are of interest. Experiments show cyclization tofunctionalization ratios X_(cycl)/X_(funct) of 1-1.5, meaning thatduring the course of the addition reaction nearly as many reactedmonomers were functionalized as were consumed without functionalizationby intramolecular cyclization. It was found to be the case for reactionconditions spanning more than one order of magnitude in thiolconcentration in the range 10⁻²<[RSH]<3×10⁻¹ M. That is, 1,2-PBfunctionalization at moderately low to very low thiol concentrationsproceeds without excessive amounts of cyclization (which would beexpected if radical I in Scheme 4 led primarily to six-member rings, asexplained earlier). The implications of this result are two-fold. First,low target levels of functionalization can be readily achieved at low orvery low [RSH], with minimal changes in the physical properties of thepolymer product resulting from cyclic/polycyclic structures. Thisenables good control of the extent of reaction and minimizes waste ofpotentially highly valuable thiol reagent. Second, the result suggestsan alternative synthetic strategy to using extremely high thiolconcentration (on the order of 10 M!) in order to achieve high degreesof functionalization (say >70%). Taking advantage of the fact thatcyclization to functionalization ratios remain in the narrow range of1-1.5 at thiol concentrations of 0.01-0.1 M, the strategy involvessynthesis of thioester compounds featuring two functional side-groupsper molecule. Deprotection and addition to 1,2-PB according to Scheme 1using thiol concentrations on the order of 0.1 M will result inincorporation of e.g. 80% side groups at 40% functionalization. Thistype of molecule is shown as compound 17 as shown in Scheme 7.

TABLE 1 Reaction Conditions and Results for 1,2-PB FunctionalizationUsing Protected Thiol PhCOSR [PB] [AIBN] Rxn time X_(funct) ^(c)X_(cycl) ^(c) M_(W) ^(d) New ¹H NMR peaks above 2.2 ppm for modified PBEntry^(a) (g/mL) [Thiol]^(b) (g/mL) (hrs) % % (kg/mol) PDI^(d) (allpeaks are broad) 92kPB3^(e,g) 0.004 1.6 0.005 6.2 40 ± 2 48 ± 3 199 1.077.71-7.43 (6H), 7.01-6.88 (2H), 4.22-4.08 (2H), 2.95-2.43 (4H)92kPB6^(f) 0.003 0.5 0.002 3.7 22 ± 2 34 ± 3 194 1.07 7.71-7.58 (4H),7.54-7.46 (2H), 7.05-6.95 (2H), 4.19-4.12 (2H), 3.90-3.82 (2H),3.77-3.67 (2H), 2.77-2.39 (4H) 92kPB8 0.004 1.2 0.001 4.4 36 ± 2 41 ± 3146 1.06 8.12-7.95 (2H), 7.53-7.12 (6H), 4.53-4.26 (2H), 2.95-2.72 (2H),2.65-2.2 (2H) 92kPB12 0.009 1.5 0.001 3.6 16 ± 1 18 ± 2 98 1.027.93-7.83 (2H), 7.88-7.80 (2H), 4.43-4.34 (2H), 2.87-2.44 (4H)92kPB13^(e) 0.003 1.9 0.001 2.0  4 ± 1  6 ± 2 122 1.07 8.55-8.46 (2H),7.70-7.63 (1H), 7.28-7.22 (1H), 3.70-3.62 (2H), 2.82-2.43 (2H) 820kPB30.003 0.3 0.001 1.5  4 ± 1  4 ± 2 1420 1.45^(h) 7.69-7.56 (4H),7.56-7.45 (2H), 7.00-6.91 (2H), 4.19-4.10 (2H), 2.92-2.80 (2H),2.74-2.49 (2H) 820kPB8^(f) 0.004 1.3 0.002 3.0 27 ± 2 36 ± 3 1200 1.258.11-7.95 (2H), 7.49-7.12 (6H), 4.52-4.28 (2H), 2.94-2.71 (2H), 2.61-2.2(2H) 820kPB12^(f) 0.007 0.2 0.002 3.0  7 ± 1 11 ± 2 579 1.48^(h)7.94-7.87 (2H), 6.87-6.79 (2H), 4.45-4.33 (2H), 2.88-2.41 (4H) 820kPB130.007 0.2 0.002 2.5  2 ± 1  3 ± 2 1310 1.26 8.55-8.46 (2H), 7.70-7.64(1H), 7.28-7.22 (1H), 3.68-3.62 (2H), 2.82-2.43 (2H) ^(a)Modified PBpolymers were named so that the prefix corresponds to the molecularweight of the starting 1,2-PB chain (98% 1,2 content), and the suffixrepresents the thioester reagent (Scheme 2) used. ^(b)In molarequivalents of 1,2-PB monomer units, estimated from the mass ratio ofthe protected thiol PhCOSR and 1,2-PB. ^(c)The fraction of reacted1,2-PB units that bear functional groups (X_(funct)) and that are notfunctionalized (X_(cycl)); refer to text. The reported uncertaintieswere calculated based on the following uncertainties for the integralsS₁, S₂, and S₃: the measurement of S₃ is ~3% accurate, and theuncertainties in S₁ and S₂ are both < 1% of (S₁ + S₂). ^(d)Measured asdescribed in Experimental section using the Waters setup, except forpolymer 92kPB12 (measurements obtained by MALLS). The 1,2-PB polymershad PDI of 1.07 and 1.26 for the 92 kg/mol and 820 kg/mol 1,2-PB chains,respectively. ^(e) ¹H NMR traces are given in FIG. 2. ^(f) ¹H NMR tracesare given in the Supplementary Information section. ^(g)GPC trace isgiven in FIG. 4. ^(h)A small amount of cross-linking is believed to haveoccurred during workup and handling of the polymer product.

TABLE 2 Reaction Conditions and Results for 1,2-PB FunctionalizationUsing 3,5-Dinitrobenzoyl Chloride (DNBC) New H NMR peaks above [PB][AIBN] Rxn time X_(funct) ^(d) X_(cycl) ^(d) M_(W) ^(e) 2.2 ppm formodified PB Entry^(a) (g/mL) [BME]^(b) (g/mL) (hrs) % % (kg/mol) PDI^(e)(all peaks are broad) 92kPB-OH^(f) 0.03 0.6 0.002 1.9 20 ± 1 28 ± 2 1511.07 3.77-3.65 (2H), 2.76-2.2 (4H) 820kPB-OH 0.02 0.4 0.001 3.0 15 ± 124 ± 2 1170 1.24 3.77-3.66 (2H), 2.76-2.3 (4H) New H NMR peaks above[PB-OH] Rxn time X_(funct) ^(d) X_(cycl) ^(d) M_(W) ^(e) 2.2 ppm formodified PB Entry^(a) (g/mL) [DNBC]^(c) [Et₃N]^(c) (hrs) % % (kg/mol)PDI^(e) (all peaks are broad) 92kPB-DNB^(f) 0.02 3.3 5.0 4.0 20 ± 1 28 ±2 158 1.08 9.24-9.20 (1H), 9.20-9.12 (2H), 4.64-4.51 (2H), 2.97-2.81(2H), 2.81-2.41 (2H) 820kPB-DNB 0.02 2.5 3.5 3.3 15 ± 1 24 ± 2 1410 1.289.24-9.20 (1H), 9.20-9.12 (2H), 4.65-4.51 (2H), 2.97-2.83 (2H),2.80-2.42 (2H) ^(a)Modified PB polymers were named so that the prefixcorresponds to the molecular weight of the starting 1,2-PB chain (98%1,2 content), and the suffix represents the functional group added.^(b)In molar equivalents of 1,2-PB monomer units. ^(c)In molarequivalents of 2-hydroxyethylthio- functionalized monomer units. ^(d)Thefraction of reacted 1,2-PB units that bear functional groups (X_(funct))and that are not functionalized (X_(cycl)); refer to text. The reporteduncertainties were calculated based on the following uncertainties forthe integrals S₁, S₂, and S₃: the measurement of S₃ is ~3% accurate, andthe uncertainties in S₁ and S₂ are both < 1% of (S₁ + S₂). ^(e)Measuredas described in Experimental section using the Waters setup. The 1,2-PBpolymers had PDI of 1.07 and 1.26 for the 92 kg/mol and 820 kg/mol1,2-PB chains, respectively. ^(f) ¹H NMR traces are given in theSupplementary Information section.

EXPERIMENTAL

Materials and Instrumentation. Except for thiobenzoic acid (Alfa Aesar,94%), carbazole (Aldrich, 95%), 4′-hydroxy-4-carbonitrile (TCl, 95%),thioacetic acid (Aldrich, 96%), allyl bromide (Aldrich, 97%), hydrazinemonohydrochloride (Acros Organics, 98%), p-toluenesulfonyl chloride(Alfa Aesar, 98%), and p-toluenesulfonic acid monohydrate (Aldrich,98.5%), all reagents were obtained at 99% purity from Aldrich, AlfaAesar, or Mallinckrodt Chemicals. 2,2′-Azobis(2-methylpropionitrile)(AIBN) was recrystallized biweekly in methanol (10 mL solvent per gAIBN) and stored at 4° C.; all other reagents were used as receivedwithout further purification. Polybutadiene polymer chains (98%1,2-content) of size 92×10³ and 820×10³ g/mol and narrow molecularweight distribution (of polydispersity index 1.07 and 1.26,respectively) were kindly donated by Dr. Steven Smith of Procter andGamble Company. ¹H and ¹³C NMR spectra were obtained using a VarianMercury 300 spectrometer (300 MHz for ¹H and 74.5 MHz for ¹³C); allspectra were recorded in CDCl₃ and referenced to tetramethylsilane.Polymer molecular weight measurements were obtained by gel permeationchromatography using one of two systems. Measurements were eithercarried out i) in tetrahydrofuran (THF) at 25° C. eluting at 0.9 mL/minthrough four PLgel 10 μm analytical columns (Polymer Labs, 10⁶ to 10³Ain pore size) connected to a Waters 410 differential refractometerdetector (λ=930 nm) or ii) in THF on two PLgel 5 μm mixed-C columns(Polymer Labs) connected in series to a DAWN EOS multi-angle laser lightscattering (MALLS) detector (Wyatt Technology, Ar laser, λ=690 nm) andan Optilab DSP differential refractometer (Wyatt Technology, λ=690 nm).In the former case, molecular weight measurements were analyzed based oncalibration using polystyrene standards; in the latter case nocalibration standards were used, and do/dc values were obtained for eachinjection by assuming 100% mass elution from the columns.

Synthesis of Benzoyl- or Acetyl-Protected Thiols (Scheme 2). Allreactions were monitored by ¹H NMR spectroscopy. Analysis of reactionmixtures was generally performed by washing a ˜1 mL aliquot with waterand extracting organic reactants and products into an appropriatesolvent, followed by solvent evaporation, and redissolving in CDCl₃ forNMR analysis. ¹³C NMR resonances of compounds 1, 3, 6, 8, 10, 12, and 13are documented below.

2-Chloroethyl-p-toluenesulfonate (1). p-Toluenesulfonyl chloride (172 g,0.884 mol) and pyridine (59 g, 0.75 mol) were added to 180 mLdichloromethane (DCM) in a 1 L round-bottom flask (RBF) which was placedin an ice bath for ca. 5 min. 1-Chloroethanol (40.3 g, 0.496 mol) wasadded slowly, and the RBF was taken out of the ice bath and left to stirat room temperature (r.t.) for 15 hrs. The reaction mixture was pouredinto a 1 L separatory funnel, washed twice with 300 mL water+50 mLpyridine, and again with 300 mL water+75 mL 36% wt aq. HCl (discardingthe aqueous phase after each wash). Removal of the solvent at reducedpressure yielded analytically pure 1 as a faint yellow, thick syrup (116g, 0.494 mol, 100% yield). ¹H NMR: δ=7.81 (d, 2 aromatic H meta to CH₃,J=8.3 Hz), 7.37 (d, 2 aromatic H ortho to CH₃, J=8.3 Hz), 4.23 (t, OCH₂,J=5.9 Hz), 3.66 (t, CH₂Cl, J=5.9 Hz), 2.46 (s, CH₃).

4′-(2-(Benzoylthio)ethoxy)[1,1′-biphenyl]-4-carbonitrile (3).4′-Hydroxy[1,1′-biphenyl]-4-carbonitrile (5.1 g, 0.025 mol),2-chloroethyl-p-toluenesulfonate (1, 9.2 g, 0.039 mol), and potassiumcarbonate (5.3 g, 0.038 mol) were stirred at 57° C. in 100 mL dimethylsulfoxide (DMSO) for 22 hrs, resulting in quantitative conversion to 2(verified by NMR analysis). Potassium chloride (2.1 g, 0.028 mol) wasadded to the reaction mixture, which was stirred 3 hrs at 85° C. toconvert the excess 1 into dichloroethane. The reaction mixture waspoured into a 1 L separatory funnel containing 300 mL water andextracted with 200 mL of 2-butanone (MEK). The aqueous phase wasextracted with another 300 mL MEK, and the organic extracts werecombined and washed 3 times with 300 mL water. Finally, solvent anddichloroethane were evaporated under reduced pressure at 80° C. to give2 (6.4 g, 0.025 mol, 100% yield) as a brown-orange syrup whichsolidifies upon cooling. To the previous product in 100 mLN,N-dimethylformamide (DMF) in a 250 mL RBF were added thiobenzoic acid(7.3 g, 0.050 mol) and potassium bicarbonate (6.8 g, 0.068 mol), and themixture was stirred at r.t. until CO₂ effervescence ceased, then at 45°C. for 4 hrs. The reaction mixture was transferred to a 1 L separatoryfunnel containing 250 mL water, extracted with 400 mL ethyl acetate, andthe organic phase was washed twice with 250 mL water before solventremoval under reduced pressure. The crude product was purified bydissolving in 300 mL ethanol at 90° C. (under slight pressure), andallowing to recrystallize by slowly cooling to r.t., then by lettingstand overnight at 4° C. Filtration of the crystals and removal ofsolvent under reduced pressure gave analytically pure 3 as ultra-fine,pale brown needles (7.9 g, 0.022 mol, 88% overall yield in 2 steps). ¹HNMR: δ=8.02-7.96 (m, 2 aromatic H ortho to COS), 7.72-7.43 (m, 3aromatic H meta and para to COS, 4 aromatic H ortho and meta to CN, and2 aromatic H meta to OCH₂), 7.05 (d, 2 aromatic H ortho to OCH₂, J=8.7Hz), 4.25 (t, OCH₂, J=6.6 Hz), 3.50 (t, SCH₂, J=6.6 Hz).

4′-(2-(2-(Benzoylthio)ethoxy)ethoxy) [1,1′-biphenyl]-4-carbonitrile (6).4′-Hydroxy[1,1′-biphenyl]-4-carbonitrile (4.9 g, 0.024 mol),2-(2-chloroethoxy)ethanol (12.7 g, 0.101 mol) and potassium phosphatetribasic (K₃PO₄.xH₂O, 22 g at ˜25% wt water, 0.078 mol) were stirred at110° C. in 150 mL DMSO for 12 hrs, resulting in quantitative conversionto 4 (verified by NMR analysis). The reaction mixture was poured into a1 L separatory funnel containing 200 mL chloroform and washed 5 timeswith 400 mL water to remove all of the chloroalcohol. The resultantorganic phase was dried with MgSO₄, filtered, and the solvent wasremoved under reduced pressure at 60° C. to afford analytically pure 4(6.5 g, 0.023 mol, 96% yield) as a pale yellow-orange syrup whichsolidifies upon cooling. To this product in 100 mL DCM at 0° C. wereadded p-toluenesulfonyl chloride (22.2 g, 0.115 mol) and pyridine (7.2g, 0.091 mol), after which the reaction vessel was allowed warm up toand left to stir at r.t. for 24 hrs. The reaction mixture wastransferred to a 500 mL separatory funnel, washed twice with 150 mLwater+25 mL pyridine, and again with 150 mL water and 40 mL 36% wt aq.HCl (discarding the aqueous phase after each wash). The organic phasewas again dried with MgSO₄, filtered, and the solvent was removed underreduced pressure at 40° C. to yield analytically pure 5 (9.5 g, 0.022mol, 95% yield), which was finally reacted to generate 6 as follows. To1.96 g (4.5 mmol) of the said product in 40 mL DMF were addedthiobenzoic acid (0.69 g, 4.7 mmol, 1.05 equiv.) and potassiumbicarbonate (1.0 g, 10 mmol), and the mixture was stirred at r.t. untilCO₂ effervescence ceased, then at 40° C. for 12 hrs. The reactionmixture was transferred to a 500 mL separatory funnel containing 200 mLwater, extracted with 100 mL ethyl acetate, and the organic phase waswashed three additional times with 200 mL water, dried with MgSO₄, andgravity filtered before solvent removal at 80° C. under reduced pressureto give analytically pure 6 as an orange syrup which crystallizes uponcooling (1.80 g, 4.5 mmol, 91% overall yield in 3 steps). ¹H NMR:δ=8.00-7.93 (m, 2 aromatic H ortho to COS), 7.72-7.39 (m, 3 aromatic Hmeta and para to COS, 4 aromatic H ortho and meta to CN, and 2 aromaticH meta to OCH₂), 7.02 (d, 2 aromatic H ortho to OCH₂, J=8.7 Hz), 4.19(t, ArOCH₂, J=4.8 Hz), 3.90 (t, ArOCH₂CH₂, J=4.8 Hz), 3.79 (t, SCH₂CH₂,J=6.5 Hz), 3.33 (t, SCH₂CH₂, J=6.5 Hz).

Thiobenzoic acid S-[2-(9-carbazolyl)ethyl]ester (8). Carbazole (15.2 g,0.086 mol), 2-chloroethyl-p-toluenesulfonate (1, 60.2 g, 0.256 mol), andpotassium hydroxide (88% wt pellets, 13.7 g, 0.215 mol) were stirred atr.t. in 300 mL DMSO for 18 hrs, resulting in quantitative conversion to7 (verified by NMR analysis). Trichloroacetic acid (TCA, 22 g, 0.135mol) and potassium chloride (20 g, 0.268 mol) were added to the reactionmixture, which was stirred 4 hrs at 100° C. to convert the excess 1 todichloroethane. After titration of the excess TCA by potassiumbicarbonate (15.5 g, 0.155 mol), the reaction mixture was poured into a1 L separatory funnel containing 180 mL water and extracted with 300 mLchloroform. The organic phase was washed twice with 400 mL water, thesolvent was evaporated under reduced pressure, and the crude product waspurified by dissolving in 475 mL boiling ethanol and allowing torecrystallize at r.t. overnight, yielding analytically pure 7 (16.5 g,0.072 mol, 83% yield) after filtration and solvent removal. To 6.8 g(0.030 mol) of this product in 110 mL DMF were added thiobenzoic acid(8.9 g, 0.061 mol) and potassium bicarbonate (8.0 g, 0.080 mol); themixture was swirled with gentle heating until CO₂ effervescence ceased,then allowed to react 4 hrs at 50° C. The reaction mixture was pouredinto a 500 mL separatory funnel containing 100 mL water, extracted with100 mL chloroform, and the organic phase was washed twice with 150 mLwater before solvent removal under reduced pressure. The crude productwas purified by first dissolving in 35 mL hot chloroform, adding 200 mLboiling ethanol, and allowing to recrystallize overnight at r.t.Filtration of the crystals and removal of solvent under reduced pressuregave analytically pure 8 as very fine, orange-pink needles (8.3 g, 0.025mol, 70% overall yield in 2 steps). ¹H NMR: δ=8.10 (d, 2 carbazole H,J=7.5 Hz), 8.03-7.96 (m, 2 aromatic H ortho to COS), 7.64-7.57 (m, 3aromatic H meta and para to COS), 7.54-7.43 (m, 4 carbazole H),7.30-7.21 (m, 2 carbazole H), 4.55 (t, NCH₂, J=7.8 Hz), 3.44 (t, SCH₂,J=7.8 Hz).

3,5-Dinitrobenzoic acid 3-(acetylthio)propyl ester (10). Potassiumbicarbonate (7.2 g, 0.072 mol) was added to 3,5-dinitrobenzoic acid(10.0 g, 0.047 mol) in 150 mL DMSO in a 500 mL RBF, and the slurry wasswirled with gentle heating until CO₂ effervescence ceased. Allylbromide (11.8 g, 0.095 mol) was added next, and the RBF was placed in anoil bath to stir at 70° C. for 2.5 hrs. The reaction mixture was pouredinto a 1 L separatory funnel containing 250 mL chloroform and washedtwice with 400 mL water (discarding the aqueous phase after each wash),yielding 9 (10.7 g, 0.042 mol, 91% yield) in >99% purity after removalof allyl bromide and solvent at 80° C. under reduced pressure. To thisproduct in 100 mL toluene was added thioacetic acid (9.8 g, 0.124 mol),and the reaction was carried out at 85° C. with argon purge via radicalmechanism using AIBN as the initiator (0.70 g, 4.3 mmol, in 0.175 gincrements at 1 hr intervals). After 6 hrs the reaction mixture waspoured into a 1 L separatory funnel containing 16 g sodium bicarbonate(NaHCO₃, 0.19 mol) in 300 mL water, extracted with 100 mL chloroform,and the organic phase was washed twice with 300 mL water before solventremoval under reduced pressure. The crude product was purified bywashing four times in 50 mL hexane at 60° C., yielding 10 in >99% purityas a viscous, dark brown syrup (9.1 g, 0.028 mol, 59% overall yield in 2steps). ¹H NMR: δ=9.24 (t, 1 aromatic H para to CO₂, J=2.1 Hz), 9.19 (d,2 aromatic H ortho to CO₂, J=2.1 Hz), 4.52 (t, OCH₂, J=6.3 Hz), 3.07 (t,SCH₂, J=6.9 Hz), 2.37 (s, CH₃), 2.15 (tt, OCH₂CH₂CH₂S, J=6.9, 6.3 Hz).

4-Hydroxybenzoic acid 2-(benzoylthio)ethyl ester (12). 4-Hydroxybenzoicacid (10 g, 0.072 mol) and 1-chloroethanol (60 g, 0.73 mol) were reactedin the bulk at 110° C. for 16 hrs with p-toluenesulfonic acidmonohydrate (2.7 g, 0.014 mol) as catalyst. The reaction mixture wastransferred to a 500 mL separatory funnel containing 5 g sodiumbicarbonate in 125 mL water, extracted with 150 mL ethyl acetate, andthe organic phase was washed 4 times with 125 mL water before solventremoval under reduced pressure, yielding 11 in ca. 97% purity (13 g,0.063 mol, 88% yield). To this product in 100 mL DMF were addedthiobenzoic acid (18 g, 0.12 mol) and potassium bicarbonate (16 g, 0.16mol), and the mixture was stirred at r.t. until CO₂ effervescenceceased, then at 50° C. for 4 hrs. The reaction mixture was poured into a500 mL separatory funnel containing 100 mL water, extracted with 100 mLchloroform, and the organic phase was washed 3 times with 150 mL waterbefore solvent removal at reduced pressure. The crude product wasfinally purified by first dissolving in 50 mL hot chloroform, adding 25mL boiling hexane, and allowing to recrystallize overnight in thefreezer. Filtration of the crystals and removal of the solvent underreduced pressure gave analytically pure 12 as a pink powder (14.5 g,0.048 mol, 67% overall yield in 2 steps). ¹H NMR: δ=8.02-7.93 (m, 2aromatic H ortho to CO₂ and 2 aromatic H ortho to COS), 7.59 (tt, 1aromatic H para to COS, J=7.5, 1.2 Hz), 7.51-7.42 (m, 2 aromatic H metato COS), 6.87 (d, 2 aromatic H meta to CO₂, J=8.7 Hz), 5.8 (br, ArOH),4.50 (t, OCH₂, J=6.5 Hz), 3.47 (t, SCH₂, J=6.5 Hz).

Thiobenzoic acid S-[3-pyridinylmethyl]ester (13). Potassium bicarbonate(12.3 g, 0.123 mol) was added to thiobenzoic acid (14.2 g, 0.097) in 200mL ethanol in a 500 mL RBF, and the slurry was swirled with gentleheating until CO₂ effervescence ceased. 3-(chloromethyl)pyridinehydrochloride (10.2 g, 0.060 mol) was added next, and the RBF was placedin an oil bath to stir at 50° C. for 2.5 hrs. The reaction mixture waspoured into a 1 L separatory funnel containing 10 g potassium carbonate(K₂CO₃, 0.072 mol) in 250 mL water, extracted with 150 mL DCM, and theorganic phase was washed twice with 250 mL water, gravity filtered, andevaporated to dryness under reduced pressure. The crude product waspurified further by washing in 50 mL hot hexane to give, after removalof leftover solvent under reduced pressure, 13 as a brown solid in ca.96% purity (11.4 g, 0.050 mol, 80% yield). ¹H NMR: δ=8.64 (d, 1 aromaticH ortho to CH₂ at the second C of the pyridine ring, J=1.8 Hz), 8.50(dd, 1 aromatic H para to CH₂ at the sixth C of the pyridine ring,J=4.8, 1.5 Hz), 7.99-7.90 (m, 2 aromatic H ortho to COS), 7.71 (ddd, 1aromatic H ortho to CH₂ at the fourth C of the pyridine ring, J=7.8,1.8, 1.5 Hz), 7.58 (tt, 1 aromatic H para to COS, J=7.5, 1.2 Hz),7.49-7.39 (m, 2 aromatic H meta to COS), 7.24 (dd, 1 aromatic H meta toCH₂ at the fifth C of the pyridine ring, J=7.8, 4.8 Hz), 4.29 (s, CH₂).

1,2-Polybutadiene Functionalization using9-[2-[(Triphenylmethyl)thio]ethyl]carbazole (14)

Synthesis of 9-(2-Chloroethyl)carbazole (7). The procedure was outlinedin the description of the preparation of 8. ¹H NMR (300 MHz, CDCl₃):δ=8.09 (d, 2 carbazole H, J=7.8 Hz), 7.50-7.37 (m, 4 carbazole H),7.29-7.20 (m, 2 carbazole H), 4.60 (t, NCH₂, J=7.2 Hz), 3.83 (t, CH₂Cl,J=7.2 Hz). ¹³C NMR (300 MHz, CDCl₃): δ=140.07, 125.91, 123.07, 120.50,119.50, 108.43, 44.64, 40.99.

Synthesis of 9-[2-[(Triphenylmethyl)thio]ethyl]carbazole (14). Potassiumcarbonate (4.4 g, 32 mmol), triphenylmethyl mercaptan (Alfa Aesar, 98%,3.1 g, 11 mmol), and 9-(2-chloroethyl)carbazole (2.1 g, 9.1 mmol) werestirred at r.t. in 50 mL DMF for 5 hrs, after which the reaction mixturewas transferred to a 500 mL separatory funnel containing 100 mL waterand extracted with 50 mL chloroform. The organic layer was washed twicewith 100 mL water, the solvent was evaporated under reduced pressure,and the crude product was purified by washing 3 times in 75 mL hotethanol. Filtration of the solids and removal of remaining solvent underreduced pressure gave analytically pure 14 as ultra-fine, white needles(3.1 g, 6.6 mmol, 72% yield). ¹H NMR (300 MHz, CDCl3): δ=8.03 (d, 2carbazole H, J=7.8 Hz), 7.43-7.14 (m, 4 carbazole H and 15 phenyl H),7.00 (d, 2 carbazole H, J=8.1 Hz), 4.06 (t, NCH₂, J=8.1 Hz), 2.75 (t,SCH₂, J=8.1 Hz). ¹³C NMR (300 MHz, CDCl3): δ=144.61, 139.76, 129.69,128.01, 126.86, 125.56, 122.79, 120.27, 119.00, 108.54, 67.39, 42.37,30.22.

Functionalization Procedure and Results. To compound 14 (0.25 g, 0.5mmol) dissolved in 10 mL chloroform in a 100 mL Schlenk tube were addedtriethylsilane (Alfa Aesar, 98%, 0.08 g, 0.7 mmol) and trifluoroaceticacid (TFA, 0.5 mL, 5% vol), and the mixture was stirred 1-2 hrs at r.t.After addition of 1,2-PB (0.2 g, 4 mmol vinyl groups, dissolved in 10 mLchloroform) and AIBN (0.03 g, 0.2 mmol), the contents of the Schlenktube were degassed in 3 freeze-pump-thaw cycles, then allowed to reactat 55° C. for 3 hrs. Following reaction, the polymer solution wastransferred to a 100 mL jar containing a small amount of BHT,concentrated by evaporation of all but the last 10 mL solvent under anargon stream, and precipitated in cold methanol. Final purification ofthe polymer was achieved by reprecipitation from a DCM solution withcold methanol (2-3 times), followed by drying to constant weight undervacuum at r.t. Reaction conditions and results for a specific exampleare given in Table A.1 (first entry).

1,2-Polybutadiene Functionalization Using Thiobenzoic acidS-[3-(9-carbazolyl)propyl]ester (16)

Synthesis of 9-Allylcarbazole (15). Carbazole (10.1 g, 0.057 mol) andpotassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11 mol) werestirred in 100 mL DMSO at 50° C. for 30 min before dropwise addition ofallyl bromide (14.7 g, 0.118 mol). After 15 min the reaction mixture waspoured into a 500 mL separatory funnel containing 100 mL chloroform andwashed 5 times with 200 mL water to give, after solvent evaporation at60° C. under reduced pressure, compound 15 in >99% purity as a darkbrown, viscous syrup which solidified upon cooling (11.9 g, 0.057 mol,100% yield). ¹H NMR (300 MHz, CDCl₃): δ=8.14-8.06 (m, 2 carbazole H),7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2 carbazole H), 6.04-5.90(m, CH═CH₂), 5.19-5.10 (m, Z—HCH═CH), 5.07-4.97 (m, E-HCH═CH), 4.92-4.85(m, NCH₂). ¹³C NMR (300 MHz, CDCl₃): δ=140.34, 132.27, 125.67, 122.90,120.33, 119.00, 116.74, 108.74, 45.21.

Synthesis of Thiobenzoic acid S-[3-(9-carbazolyl)propyl]ester (16).Thiobenzoic acid (30 g, 0.20 mol) was added to 9-allylcarbazole (11.9 g,0.057 mol) in 100 mL toluene, and the reaction was carried out at 90° C.with argon purge via radical mechanism using AIBN as the initiator (1.8g, 11 mmol, in 300 mg increments at 1 hr intervals). After 6 hrs thereaction mixture was poured into a 1 L separatory funnel containing 20 gsodium bicarbonate (NaHCO₃, 0.24 mol) in 250 mL water, extracted with100 mL chloroform, and the organic phase was washed twice with 200 mLwater before solvent removal under reduced pressure. The crude productwas subsequently washed in 100 mL hot hexane, 150 mL ethanol, andfinally 150 mL of 15:1 ethanol:chloroform. Evaporation of leftoversolvent at 80° C. under reduced pressure yielded compound 16 in ca. 90%purity as a dark brown, viscous syrup which solidified upon cooling(9.35 g, 0.024 mol, 42% yield, ˜10% wt dibenzoyl disulfide). ¹H NMR (300MHz, CDCl₃): δ=8.10 (d, 2 carbazole H, J=8.1 Hz), 8.00-7.95 (m, 2aromatic H ortho to COS), 7.62-7.41 (m, 3 aromatic H meta and para toCOS plus 4 carbazole H), 7.27-7.19 (m, 2 carbazole H), 4.43 (t, NCH₂,J=6.9 Hz), 3.06 (t, SCH₂, J=6.9 Hz), 2.26 (tt, NCH₂CH₂CH₂S, J=6.9, 6.9Hz). ¹³C NMR (300 MHz, CDCl₃): δ=191.56, 140.25, 136.88, 133.50, 128.65,127.23, 125.75, 122.91, 120.41, 119.00, 108.55, 41.65, 28.95, 26.41.

Functionalization Procedure and Results. Reaction conditions and resultsfor a specific example are given in Table A.1 (second entry).

TABLE A1 Reaction Conditions and Results for 1,2-PB FunctionalizationUsing Compounds 14 and 16 [PB] [AIBN] Rxn time X_(funct) ^(c) M_(W) ^(d)New H NMR peaks above 2.2 ppm for modified PB Entry^(a) (g/mL)[Thiol]^(b) (g/mL) (hrs) % (kg/mol) PDI^(d) (all peaks are broad)820kPB14 0.011 0.1 0.002 2.9 6 945 2.08 8.12-8.04 (2H), 7.52-7.39 (4H,7.27-7.19 (2H), 4.56-4.43 (2H), 2.97-2.83 (2H) 92kPB16 0.003 1.1 0.0033.0 19 187 1.34 8.15-8.03 (2H), 7.56-7.37 (4H, 7.28-7.15 (2H),4.50-4.27(2H), 2.62-2.30 (4H) ^(a)Modified PB polymers were named sothat the prefix corresponds to the molecular weight of the starting1,2-PB chain, and the suffix represents the reagent used. ^(b)In molarequivalents of 1,2-PB monomer units. ^(c)The fraction of reacted 1,2-PBunits that bear functional groups (refer to text). ^(d)Measurements asdescribed in Experimental section using the Waters setup (the 1,2-PBprepolymers had PDI values of 1.07 and 1.26 for the 92 kg/mol and 820kg/mol chains, respectively.

General Procedure for 1,2-PB Functionalization Using a Protected ThiolPhCOSR (Scheme 1). To the thioester PhCOSR (1-4 mmol) dissolved in 25-75mL DMF in a 250 mL RBF were added hydrazine monohydrochloride (ca. 4equiv., 4-16 mmol) and sodium acetate (ca. 8 equiv., 8-32 mmol). The RBFwas purged with argon for ca. 10 min and left to stir at r.t. for 2-4hrs, resulting in 95-100% cleavage of the thioester (verified by NMRanalysis). The thiol product was extracted into 30-40 mL chloroformafter addition of 100 mL water; the organic phase was washed 4 timeswith 150 mL water, and transferred into a 100 mL Schlenk tube containing1,2-PB (0.1-0.2 g, 2-4 mmol, dissolved in 10 mL chloroform) and AIBN(50-250 mg, 0.3-1.5 mmol). The contents of the Schlenk tube weredegassed in 3 freeze-pump-thaw cycles, and then allowed to react at 55°C. for 2-6 hrs. Following reaction, the polymer solution was transferredto a 100 mL jar containing a small amount of2,6-ditert-butyl-4-methylphenol (BHT), concentrated by evaporation ofall but the last 10 mL solvent under an argon stream, and precipitatedwith cold methanol. Final purification of the polymer was achieved byreprecipitation from a DCM or THF solution (containing ca. 1% wt BHT)with cold methanol (repeated 2-4 times), followed by drying to constantweight under vacuum at r.t.

General Procedure for 1,2-PB Functionalization Using an Acyl ChlorideRCOCl (Scheme 3). To 1,2-PB (0.1-0.5 g, 2-9 mmol) dissolved in 15-30 mLTHF in a 100 mL Schlenk tube was added a 10 mL THF solution of2-mercaptoethanol (BME, 0.5-2 equiv., 1-20 mmol) and AIBN (15-50 mg,0.1-0.3 mmol). The contents of the Schlenk tube were degassed in 3freeze-pump-thaw cycles, and then allowed to react at 55° C. for 2-3hrs. Following reaction, the polymer solution was transferred to a 100mL jar containing a small amount of BHT and precipitated in coldmethanol. The polymer was purified by reprecipitation from a THFsolution (containing ca. 1% wt BHT) with cold methanol (repeated 1-2times), followed by drying to constant weight under vacuum at r.t. Tothe 2-hydroxyethylthio-functionalized 1,2-PB polymer (0.1-0.5 g)dissolved in 10-25 mL DCM in a 100 mL RBF were added triethylamine(Et₃N, 3-5 mol. equiv. of functionalized monomer units) and the acylchloride RCOCl (2.5-3 mol. equiv. of functionalized monomer units), andthe reaction mixture was stirred 3-4 hrs at r.t. Following reaction, thepolymer solution was transferred to a 100 or 250 mL jar containing asmall amount of BHT, washed with 50-100 mL water and again with 50-100mL aqueous sodium bicarbonate (discarding the wash each time),concentrated by evaporation of all but the last 10 mL DCM under an argonstream, and finally precipitated with cold methanol. Final purificationof the polymer was achieved by reprecipitation from a DCM solution(containing ca. 1% wt BHT) with cold methanol (repeated 2-3 times),followed by drying to constant weight under vacuum at r.t.

Alkylation of Nucleophiles to Introduce Primary Halide or AlcoholMoieties. To generate ω-chloroalkyl or ω-bromoalkyl derivatives,alkylation of nucleophiles is usually done using α,ω dibromo- ordichloro-alkanes, e.g., reaction of 4′-hydroxy-biphenyl-4-carbonitrilewith 1,6-dibromohexane²⁵ or carbazole with 1,2-dichloroethane²⁶.Unfortunately, when using these reagents bisubstitution is always anissue. In addition, in the case of very basic nucleophiles (e.g.deprotonated carbazole), elimination competes effectively; hence, yieldstend to be low and product purification usually requires columnchromatography. Yields of >50% were not achieved for the synthesis of 7according to published methods²⁶ using KOH/K₂CO₃ as base in 1,2dichloroethane with tetrabutylammonium bromide as phase-transfercatalyst. Chloroethylation of nucleophiles with2-chloroethyl-p-toluenesulfonate (1) in DMSO at low to moderatetemperatures overcame both problems stated above. First, the use ofp-toluenesulfonate (tosylate) as leaving group and of a polar aproticsolvent both favor substitution over elimination²⁷; second, becausetosylate is a significantly better leaving group than chlorine,quantitative conversion of both carbazole and4′-hydroxy-biphenyl-4-carbonitrile to the chloroethyl derivatives(compounds 7, 2) was achieved without measurable formation ofside-products. Excess 1 could be reacted quantitatively to1,2-dichloroethane with KCl in a few hours, so that product inquantitative yields and >95% purity could be obtained by mereliquid-liquid extraction and removal of solvent and dichloroethane atreduced pressure.

Alkylation of nucleophiles to generate ω-hydroxyalkyl derivatives isusually done using ω-bromo-1-alkanols or ω-chloro-1-alkanols with K₂CO₃or NaH as base in DMF, acetone, or ethanol as solvent (for instance,alkylation of 4′-hydroxy-biphenyl-4-carbonitrile with bromodecanol²⁸ orchlorohexanol²⁹). Published yields for such reactions are usually <85%,and column chromatography is typically necessary for isolation of theproduct. Here it was discovered that alkylation of4′-hydroxy-biphenyl-4-carbonitrile with commercially availableH(OCH₂CH₂)_(n)Cl (n=1-3, inexpensively available from Wako Chemicals) inDMSO with K₃PO₄ as base gave quantitative conversion, and that product(compound 4 or analog) in >99% purity could be obtained by mere washesdue to the good water solubility of the chloride reagent.

¹³C NMR Resonances of Select Compounds

All ¹³C NMR spectra were obtained using a Varian Mercury 300spectrometer (corresponding to 74.5 MHz for ¹³C), recorded in CDCl₃, andreferenced to tetramethylsilane. Information compiled in the SpectralDatabase for Organic Compounds (available online athttp://riodb01.ibase.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi) wasused in the process of assigning ¹³C NMR resonances.

2-Chloroethyl-p-toluenesulfonate (1). ¹³C NMR: δ=145.30 (e), 132.44 (b),130.00 and 127.97 (c and d), 69.02 (f), 40.83 (g), 21.67 (a).

4′-(2-(Benzoylthio)ethoxy)[1,1′-biphenyl]-4-carbonitrile (3). ¹³C NMR:δ=191.40 (e), 159.00 (j), 145.11 (n), 136.64 (d), 133.69 (a), 132.57(p), 131.89 (m), 128.70 and 127.30 (b and c), 128.43 (l), 127.13 (o),119.09 (r), 115.21 (k), 110.14 (q), 66.70 (g), 28.13 (f).

4′-(2-(2-(Benzoylthio)ethoxy)ethoxy) [1,1′-biphenyl]-4-carbonitrile (6).¹³C NMR: δ=191.54 (e), 159.35 (j), 145.12 (n), 136.82 (d), 133.48 (a),132.54 (p), 131.63 (m), 128.61 and 127.23 (b and c), 128.30 (l), 127.07(o), 119.10 (r), 115.22 (k), 110.06 (q), 70.05 and 69.38 (h and i),67.50 (g), 28.65 (f).

Thiobenzoic acid S-[2-(9-carbazolyl)ethyl]ester (8). ¹³C NMR: δ=191.73(e), 140.07 (h), 136.71 (d), 133.73 (a), 128.74 and 127.35 (b and c),125.91 (j), 122.98 (m), 120.40 (l), 119.26 (k), 108.74 (i), 42.42 (g),27.28 (f).

3,5-Dinitrobenzoic acid 3-(acetylthio)propyl ester (10). ¹³C NMR:δ=195.36 (b), 162.49 (f), 148.67 (i), 133.81 (g), 129.52 (h), 122.47(j), 65.21 (e), 30.64 (a), 28.68 and 25.50 (c and d).

4-Hydroxybenzoic acid 2-(benzoylthio)ethyl ester (12). ¹³C NMR: δ=191.42(e), 166.27 (h), 160.24 (l), 136.65 (d), 133.68 (a), 132.09 (j), 128.70and 127.32 (b and c), 122.13 (i), 115.28 (k), 63.11 (g), 27.86 (f).

Thiobenzoic acid S-[3-pyridinylmethyl]ester (13). ¹³C NMR: δ=190.74 (e),150.14 (h), 148.62 (i), 136.48 and 136.42 (d and k), 133.70 and 133.65(a and g), 128.71 and 127.31 (b and c), 123.46 (j), 30.38 (f).

¹H NMR Spectra of Select Functionalized Polymers

All spectra were taken in CDCl₃, resulting in a solvent peak in eachcase at δ=7.24 ppm. Peaks near 1.6 ppm correspond to water, and visiblepeaks at δ=6.97, 2.27, and 1.43 ppm belong to BHT. RepresentativeSpectra are shown in FIGS. 1-6.

Statements Regarding Incorporation By Reference and Variations

All references throughout this application, for example patent documentsincluding issued or granted patents or equivalents; patent applicationpublications; and non-patent literature documents or other sourcematerial; are hereby incorporated by reference herein in theirentireties, as though individually incorporated by reference, to theextent each reference is at least partially not inconsistent with thedisclosure in this application (for example, a reference that ispartially inconsistent is incorporated by reference except for thepartially inconsistent portion of the reference).

When a group of substituents is disclosed herein, it is understood thatall individual members of those groups and all subgroups, including anyisomers and enantiomers of the group members, and classes of compoundsthat can be formed using the substituents are disclosed separately. Whena Markush group or other grouping is used herein, all individual membersof the group and all combinations and subcombinations possible of thegroup are intended to be individually included in the disclosure. When acompound is described herein such that a particular isomer or enantiomerof the compound is not specified, for example, in a formula or in achemical name, that description is intended to include each isomer andenantiomer of the compound described individually or in any combination.When an atom is described herein, including in a composition, anyisotope of such atom is intended to be included. Specific names ofcompounds are intended to be exemplary, as it is known that one ofordinary skill in the art can name the same compounds differently. Everyformulation or combination of components described or exemplified hereincan be used to practice the invention, unless otherwise stated. Whenevera range is given in the specification, for example, a temperature range,a time range, or a composition range, all intermediate ranges andsubranges, as well as all individual values included in the ranges givenare intended to be included in the disclosure.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art, insome cases as of their filing date, and it is intended that thisinformation can be employed herein, if needed, to exclude (for example,to disclaim) specific embodiments that are in the prior art. Forexample, when a compound is claimed, it should be understood thatcompounds known in the prior art, including certain compounds disclosedin the references disclosed herein (particularly in referenced patentdocuments), are not intended to be included in the claim.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention. It will be apparent to oneof ordinary skill in the art that methods, devices, device elements,materials, procedures and techniques other than those specificallydescribed herein can be applied to the practice of the invention asbroadly disclosed herein without resort to undue experimentation. Allart-known functional equivalents of methods, devices, device elements,materials, procedures and techniques described herein are intended to beencompassed by this invention. Whenever a range is disclosed, allsubranges and individual values are intended to be encompassed. Thisinvention is not to be limited by the embodiments disclosed, includingany shown in the drawings or exemplified in the specification, which aregiven by way of example or illustration and not of limitation.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments, exemplary embodiments and optional features, modificationand variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention as defined by theappended claims. The specific embodiments provided herein are examplesof useful embodiments of the present invention and it will be apparentto one skilled in the art that the present invention may be carried outusing a large number of variations of the devices, device components,methods steps set forth in the present description. As will be obviousto one of skill in the art, methods and devices useful for the presentmethods can include a large number of optional composition andprocessing elements and steps.

Many of the molecules disclosed herein contain one or more ionizablegroups [groups from which a proton can be removed (e.g., —COON) or added(e.g., amines) or which can be quaternized (e.g., amines)]. All possibleionic forms of such molecules and salts thereof are intended to beincluded individually in the disclosure herein. With regard to salts ofthe compounds herein, one of ordinary skill in the art can select fromamong a wide variety of available counterions those that are appropriatefor preparation of salts of this invention for a given application. Inspecific applications, the selection of a given anion or cation forpreparation of a salt may result in increased or decreased solubility ofthat salt.

Every formulation or combination of components described or exemplifiedherein can be used to practice the invention, unless otherwise stated.

Whenever a range is given in the specification, for example, atemperature range, a time range, or a composition or concentrationrange, all intermediate ranges and subranges, as well as all individualvalues included in the ranges given are intended to be included in thedisclosure. It will be understood that any subranges or individualvalues in a range or subrange that are included in the descriptionherein can be excluded from the claims herein.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art asof their publication or filing date and it is intended that thisinformation can be employed herein, if needed, to exclude specificembodiments that are in the prior art. For example, when composition ofmatter are claimed, it should be understood that compounds known andavailable in the art prior to Applicant's invention, including compoundsfor which an enabling disclosure is provided in the references citedherein, are not intended to be included in the composition of matterclaims herein.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. In each instanceherein any of the terms “comprising”, “consisting essentially of” and“consisting of” may be replaced with either of the other terms. Theinvention illustratively described herein suitably may be practiced inthe absence of any element or elements, limitation or limitations whichis not specifically disclosed herein.

One of ordinary skill in the art will appreciate that startingmaterials, biological materials, reagents, synthetic methods,purification methods, analytical methods, assay methods, and biologicalmethods other than those specifically exemplified can be employed in thepractice of the invention without resort to undue experimentation. Allart-known functional equivalents, of any such materials and methods areintended to be included in this invention. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention as defined by the appended claims.

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We claim:
 1. A functionalized thioester made by a method of preparing afunctionalized thioester comprising: (a) reacting a nucleophilicstarting material having a desired functional group with anonsymmetrical bifunctional linker molecule, forming a functionalizedintermediate; and (b) reacting the functionalized intermediate with athiol acid to form a functionalized thioester.
 2. A functionalizedthioester having the following formula:

wherein R is a functional group and COR′ is a protecting group that isreadily cleaved to provide a functional thiol that may be used withoutisolation to perform thiol-ene coupling.
 3. The functionalized thioesterof claim 2, wherein the protecting group is an acetyl or benzoyl group.4. The functionalized thioester of claim 2, wherein the functional groupis selected from the group consisting of: amino acid, peptide,polypeptide, nucleic acid, lipid, carbohydrate, carbazole, benzoate,phenol, pyridine, cyanobiphenyl, perfluorocarbon, polyethylene oxide(PEO) and polypropyleneoxide (PPO) groups